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AssigneeCenter for Blood Research, Inc.
InventorsTimothy A. Springer, Motomu Shimaoka, Chafen Lu
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The present invention provides a method for stabilizing a protein in a desired conformation by introducing at least one disulfide bond into the polypeptide. Computational design is used to identify positions where crysteine residues can be introduced to form a disulfide bond in only one protein conformation, and therefore lock the protein in a given conformation. Accordingly, antibody and small molecule therapeutics are selected that are specific for the desired protein conformation. The invention also provides modified integrin I-domain polypeptides that are stabilized in a desired conformation. The invention further provides screening assays and therapeutic methods utilizing the modified integrin I-domains of the invention.
A method for inhibiting αL-mediated interaction with ICAM-1 in an inflammatory disorder or an autoimmune disease in a subject comprising administering to said subject a therapeutically effective amount of an antibody, or an antigen binding fragment thereof, which selectively binds only to a modified integrin αL I-domain polypeptide of SEQ ID NO:2 stabilized in the open conformation by the substitution K287C/K294C, but not to the modified integrin αL I-domain of SEQ ID NO:2 stabilized in the closed conformation, said mutation is based on the mature form of SEQ ID NO:2, thereby inhibiting αL-mediated interaction with ICAM-1 in a subject.
Dependencies are inferred from the claim text.